This invention pertains to an osmotic device containing alprazolam and an anti-psychotic agent. More particularly, it pertains to an osmotic device tablet that provides a controlled release of alprazolam and an immediate release of an anti-psychotic agent, wherein the tablet is suited for once-daily administration in the treatment of psychological disorders.
Clinical depression is a disorder characterized by low self-esteem, guilt, self-reproach, introversion, sadness, despair, sleeping disorders, eating disorders or discouragement. Depression generally causes a lower or decrease of a person""s function. Anxiety is a disorder characterized by responses to anticipation of unreal or imagined danger and is know to cause increased heart rate, altered respiration rate, sweating, trembling, weakness, or fatigue. Psychosis is a disorder characterized by gross impairment in reality perception as evidenced by delusions, hallucinations, markedly incoherent speech, or disorganized and agitated behavior without apparent awareness on the part of the person of the incomprehensibility of his behavior.
Major depression and anxiety occur concomitantly in more patients than either one alone. When these disorders occur together, they are associated with more severe symptoms, increased impairment of function, a longer chronic course, poorer outcome, and a higher incidence of suicide.
Antidepressants, such as alprazolam, have been tested for the treatment of depression and symptoms of anxiety. Anti-psychotic agents, such as risperidone, are used for the treatment of psychosis. On occasion, a person suffering from depression or anxiety and psychosis will be prescribed an antidepressant agent and an anti-psychotic agent. However, mixed results with this type of combination have been reported in the literature. For example, sometimes no therapeutic advantage for the combination is observed and at other times, the combination therapy results in additional, excessive or previously unobserved side effects.
Alprazolam is commercially available in tablet dosage form from Alphapharm, Chelsea Labs, Geneva Pharmaceuticals, Lederle Laboratories, Mylan Pharmaceuticals, Novopharm, Pharmacia Upjohn, Purepac Pharmaceuticals, Roxane, Watson Laboratories, and Zenith Goldline. However, those of skill in the art have not been able to develop a combination formulation containing alprazolam and an anti-psychotic drug. Moreover, there has been no suggestion in the art of a combination osmotic device as claimed herein.
Controlled release capsule dosage forms and osmotic device dosage forms are generally known by the skilled artisan to provide different release profiles. Effective therapy with antidepressants and anxiolytic agents is dependent upon a careful control of the blood plasma levels of these agents, and therefore, upon the release profiles of these agents from their respective dosage forms.
Osmotic devices and other tablet formulations are known for their ability to provide a controlled release of a wide range of drugs. Such osmotic devices and other tablet formulations are disclosed in U.S. Pat. No. 4,014,334 to Theeuwes et al., U.S. Pat. No. 4,576,604 to Guittard et al., Argentina Patent No. 234,493, U.S. Pat. No. 4,673,405 to Guittard et al., U.S. Pat. No. 5,558,879 to Chen et al., U.S. Pat. No. 4,810,502 to Ayer et al., U.S. Pat. No. 4,801,461 to Hamel et al., U.S. Pat. No. 5,681,584 to Savastano et al., U.S. Pat. No. 3,845,770, U.S. Pat. No. 6,004,582 to Faour et al., and Argentina Patent No. 199,301, the entire disclosures of which are hereby incorporated by reference.
These references, however, do not disclose osmotic devices that provide the specific plasma profiles or release profiles for alprazolam (APZ) that the present invention provides. Moreover, the prior art does not disclose an osmotic device containing a combination of alprazolam with an anti-psychotic agent, wherein the alprazolam and anti-psychotic agent are delivered according to specific release profiles. The delivery of the drugs according to the pharmacokinetics disclosed herein renders the claimed osmotic device useful for treating a range of psychological disorders.
Alprazolam possesses low water solubility and is therefore difficult to formulate into a controlled release dosage form that provides an approximately complete delivery of the alprazolam over an extended period of time. The present inventors have succeeded in developing an osmotic device dosage form that provides a controlled release of alprazolam over an extended period of time for once-daily administration. Together with an anti-psychotic agent, the alprazolam provides a therapeutic system for the treatment of psychoses and other neurological/psychological/psychiatric disorders.
In one aspect, the present invention provides an osmotic device comprising:
a core comprising a therapeutically effective amount of alprazolam and at least one osmotic agent or osmopolymer; and
a semipermeable membrane surrounding the core and having a passageway there through;
wherein the core provides a controlled release of APZ, and at least 60% of the APZ is released within 10 hours after exposure of the osmotic device to an aqueous solution.
Another aspect of the present invention provides an osmotic device for the delivery of APZ and an anti-psychotic agent comprising:
a core comprising a therapeutically effective amount of alprazolam and at least one osmotic agent or osmopolymer;
a semipermeable membrane surrounding the core and having a passageway there through; and
an external coat comprising a therapeutically effective amount of an anti-psychotic agent;
wherein the core provides a controlled release of APZ, and at least 60% of the APZ is released within 10 hours after exposure of the osmotic device to an aqueous solution, and the external coat provides a rapid release of the anti-psychotic agent, and at least 75% of the anti-psychotic agent is released within 1 hour after exposure of the osmotic device to an aqueous solution.
In still other preferred embodiments, the external coat is applied by spray coating or compression coating. By spray coating rather than compression coating the external coat, a thinner external coat, and therefore a smaller osmotic device, is formed.
Another aspect of the invention provides a method of treating depression, anxiety and/or psychosis in a mammal, the method comprising the step of administering an osmotic device which provides a controlled release of APZ from its core and a rapid release of an anti-psychotic agent from an external coat, wherein at least 75% of the anti-psychotic agent is released within about 40 minutes, and at least about 60% of the APZ is released within about 1 hour after administration.
In other embodiments, the osmotic device provides: a) a APZ release profile similar to that shown in FIG. 1; or b) a APZ plasma profile similar to that shown in FIG. 2. In still other embodiments, the release of APZ and/or the anti-psychotic agent has a delayed onset.
Other embodiments include those wherein the anti-psychotic agent is selected from the group consisting of risperidone, olanzapine, clozapine, sertindole, ziprasidone, quetiapine, sulpiride, pimozide, clothiapine, molindone, loxapine, trifluoperazine, haloperidol, flupenthixol, chlorpromazine, chlorprothixene, clopenthixol, droperidol, perphenazine, fluphenazine, lithium, mesoridazine, spiperone, promazine, prochlorperazine, thioridazine, thiothixene, triflupromazine and raclopride.
According to other embodiments, the anti-psychotic agent is administered once daily at a dose of: a) risperidone-5 to 10 mg per day; b) olanzapine-5 to 20 mg, 0.25-50 mg, 1-30 mg, or 1-25 mg per day; c) clozapine-100 to 400 mg, 12.5-900 mg, or 150-450 mg per day; d) sertindole-15 to 20 mg per day or 0.0001 to 1.0 mg/kg of body weight per day; e) ziprasidone-80 to 160 mg, 5 to 500 mg or 50 to 100 mg per day; f) quetiapine-150 to 600 mg or 1.0-40 mg/kg of body weight per day; g) sulpiride-50 to 100 mg per day; h) pimozide-2 to 4 mg per day; or i) clothiapine-40 mg per day.
The osmotic device generally delivers the anti-psychotic agent to the upper GI tract and the alprazolam to the middle to lower GI tract.
Other features, advantages and embodiments of the invention will become apparent to those skilled in the art by the following description, accompanying examples.